Three-gene signature predicts disease progression of non-muscle invasive bladder cancer

Abstract

Abstract.The clinical grades and staging methods currently employed for bladder cancer (BC) are inadequate for assessing treatment outcomes for non-muscle invasive bladder cancer (NMIBC). We have developed a clinically applicable quantitative real-time PCR (qPCR) gene signature to predict the progression of NMIBC. Three genes not previously described for BC were selected from our published progression-related gene classifier data set. Data were drawn from a previous study population and from new cases. Primary NMIBC tissue specimens (n=193) were analyzed by qPCR. Risk scores were then used to rank specimens into high-and low-risk signature groups based on their gene expression. The Kaplan-Meier method and a multivariate Cox regression model were used to identify the prognostic value of the three-gene signature for both recurrence and progression. The Kaplan-Meier estimates revealed significant differences in time-to-recurrence and progression between low-and high-risk signatures (log-rank test, p=0.011 and p<0.001, respectively). The multivariate Cox regression analysis showed that the three-gene risk signature is an independent predictor of bladder tumor progression (hazard ratio, 4.268; 95% CI, 1.542-11.814; p=0.005). In conclusion, our three-gene signature was found to be closely associated with progression among patients with NMIBC. IntroductionBladder cancer (BC), the incidence and mortality of which increases directly with age, is a heterogeneous disease that affects approxi mately 68,000 people in the United States annually (1). In Korea, BC is the second most common urological malignancy and is about five times more common in male as compared to female individuals (2). Patients diagnosed with non-muscle invasive bladder cancers (NMIBC) may have indolent, albeit recurrent, disease. However, NMIBC patients are required to receive frequent cystourethroscopy, which is inconvenient for patients. Additionally, they may experience progression to muscle invasive bladder cancer (MIBC), which potentially has a narrow window-of-cure and requires aggressive treatment (3). Therefore, predicting the course of the disease is of great value to both patients and urologists, in order for adequate management of NMIBC to occur. For example, early radical cystectomy has a superior 5-year survival rate compared to bladder-sparing surgery (4). The development of accurate and reliable biological markers would be useful for assessing aggressiveness and for predicting the prognosis of NMIBC.Previously, we undertook a microarray analysis of specimens derived from 103 primary NMIBC patients and identified an eight-gene progression-related gene classifier (5). Although there have been numerous attempts to establish prognostic markers for NMIBC (3,(6)(7)(8)

A potential prognostic lncRNA signature for predicting survival in patients with bladder urothelial carcinoma

“…Considerable efforts have been made during the past years to identify expression-based prognostic biomarkers for bladder cancer at protein-coding genes and miRNAs levels [ 45 – 47 ]. More recently, accumulated evidence indicates that dysregulated lncRNAs are implicated in various tumorigenesis processes including proliferation, invasion and apoptosis by acting as tumor oncogenes or suppressor, which has developed a new area for biomarkers.…”

MicroRNA Expression Profile Identifies High Grade, Non-Muscle-Invasive Bladder Tumors at Elevated Risk to Progress to an Invasive Phenotype

“…There have been numerous reports of genome-wide gene expression profiling of different bladder tumor groups highlighting the expression of clusters of genes indicative of specific tumor type [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], tumor behavior [ 22 , 23 , 24 , 25 ] or response to chemotherapeutic agents [ 26 , 27 ]. A similar approach has been taken with microRNA (miRNA) profiling where altered expression of specific miRNAs has been linked to bladder tumorigenesis [ 14 , 28 , 29 , 30 , 31 , 32 ] including predictors of outcome [ 33 , 34 , 35 , 36 ] and progression to muscle-invasive (MI) disease [ 37 ].…”

Elevated CELSR3 expression is associated with hepatocarcinogenesis and poor prognosis

“…CELSR receptor 3 (CELSR3) contains nine cadherin domains, which act as homophilic binding regions, and seven EGF-like domains involved in receptor-ligand interactions and cell adhesion, and is considered to serve a key role in cell-cell contacts ( 9 , 10 ). Dysregulation of CELSR3 DNA methylation is associated with several types of cancer, including pancreatic, hepatic, bladder and renal carcinomas ( 11 – 14 ). It has been reported that CELSR3 displays a cancer-specific pattern, and a 3.04-fold increase in its expression has been reported in tumor-associated stellate cells compared with inflammation-associated stellate cells ( 14 ).…”